The autoimmune lymphoproliferative syndrome (ALPS) is a human disorder due to defective lymphocyte apoptosis resulting in abnormalities in lymphocyte homeostasis. This produces a combination of lymphadenopathy, autoimmunity and increased risk of lymphoma. The diagnostic criteria used to diagnose ALPS include a triad of findings: lymphadenopathy, increased circulating alpha-beta double negative T cells and defective in vitro Fas mediated lymphocyte apoptosis. The majority of patients with ALPS have been found to have a heterozygous mutation in the gene encoding Fas (CD95) while a small number of patients have been found to have mutations in Fas ligand or caspase 10. However, a sizeable number of ALPS patients do not have mutations in the genes noted about and are categorized as having ALPS type 3 with an uncharacterized defect. We have begun a systematic evaluation of ALPS type 3 patients by first collecting all the various laboratory data that has been identified as abnormal in ALPS type 1a to see if these findings differ in ALPS type 3 patients. In addition, we have begun a systenatic evaluation of intracellular proteins involved with the apoptotic process. These are targeted at assessing the assemblage of the Death Inducing Signalling Complex (DISC) and downstream events and proteins that control the apoptotic cascade that ultimately results in cell death. We are also attempting to identify ALPS type 3 patients who have relatives with similar clinical findings in an attempt to identify genetic links to disease development. Finally, we are embarking on an expression microarray evaluation of ALPS type 3 patients focusing intitially on non-activated T cells with plans to also evaluate activated T cells.